DESCRIPTION: The investigators propose theoretical and experimental studies of the effects of flow dynamics on the initial interactions of platelet glycoprotein IB-alpha and von Willebrand's factor bound to a solid substrate, as further described by their abstract: "This research proposal deals with the initial interactions between flowing platelets and adhesive surfaces. The research plan is divided in three different specific aims. 1) The first specific aim addresses the problem of the transport of platelets toward a reacting surface as a function of the flow field. There is a discrepancy between the existing theory and the experimental results obtained with current technology. Existing theoretical models predict a linear relation between platelet concentration in the bulk and platelet flux in the boundary layer. It is proposed to investigate the properties of the GP Iba-vWF interaction as an experimental tool to determine the amount of platelets flowing in close proximity to the thrombogenic surface. Numerical simulations will include a function for platelet size and platelet geometry in the transport process. (2) The second specific aim deals with the micromechanics of GP Iba-vWF and interactions where the integrin aIIbB3 participates. Under flow, the basic difference reported is that aIIbB3 (with fibrinogen and vWF) supports permanent adhesion, while the GP Iba-vWF interaction is transient (translocation). It is hypothesized in this proposal that one of the main differences between these interactions is their resistance to tensile stress. Experimental studies will be directed to understand the effect of shear stress on the dissociation constant for these interactions; to do this the density of the ligand on the surface will be lowered, aiming for single molecule interactions, also a recombinant A1 domain of vWF will be used at low concentrations. For the analysis of the process, the platelet will be modeled as an oblate spheroid, forces will be balanced at momentary platelet arrest on the surface. (3) The last specific aim of the proposal consists in the analysis and modeling of the association and dissociation constants under flow. It is proposed, a general formulation for the interaction of adhesion receptor molecules bound to a moving cell and ligand molecules adsorbed to a fixed surface. With this approach a new "convective" model will be generated that is closer to in vivo models than the traditionally used diffusion models. The proposed project will help to understand better the early interactions of platelets with adhesive surfaces. Understanding these processes, by the development of specific experimental and analytical tools, will help to plan better therapeutic strategies in thrombosis and hemostasis; because of the large morbidity and mortality due to thrombosis related disorders, this area is one of the priorities in public health."